Highlights from Recent Cancer Literature
Journal: Cancer Research (2016)

Identifying synthetic lethal interactions with oncogenic KRAS has been challenging. One potential hurdle may be associated with phenotype diversity among KRAS mutant cancers, both between and within disease lineages. Utilizing 106 non-small-cell lung cancer cell (NSCLC) lines to interrogate 4,725 biological processes, Kim and colleagues showed acute and specific cell-autonomous addiction of KRAS-mutant NSCLC cells to receptor-dependent nuclear export. Specifically, inhibition of the export receptor XPO1/CRM1 with the drug Selinexor revealed a robust synthetic-lethal interaction both in vitro and in vivo. The primary mechanism underpinning XPO1 inhibitor sensitivity was intolerance to accumulation of nuclear IκBα/NFKBIA, with consequent inhibition of NF-κB transcription factor activity. Surprisingly, a minority of KRAS mutant NSCLC cell lines showed intrinsic resistance to XPO1 inhibition, mediated through the FSTL5–Hippo pathway. These findings support a precision medicine trial to test XPO1 inhibitors in lung cancer.Kim J, McMillan E, Kim HS, Venkateswaran N, Makkar G, Rodriguez-Canales J, et al. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature 2016;538:114–7.Schmitt and colleagues identified a novel p53-inducible long noncoding RNA (lncRNA) called DINO that binds and stabilizes p53, directing a feed forward DNA damage response loop. DINO promoted this p53-dependent DNA damage response by amplifying the transcriptional program directly at p53 response gene promoters. The organismal role of mouse Dino was validated ex vivo and in vivo by generating a Dino conditional knockout mouse. The DNA damage response was blunted to canonical DNA damaging agents in two different cell types derived from these mice, also shown by lethal whole body irradiation experiments. These cellular and organism effects were mediated by p53-induced apoptotic pathways. The susceptibility of Dino knockout mice to tumors was not reported, but presumably resembled some subset of p53 knockout spectra. These data show a broader function for RNAs in regulating p53 signaling.Schmitt AM, Garcia JT, Hung T, Flynn RA, Shen Y, Qu K, et al. An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet 2016 Sep 26. doi: 10.1038/ng.3673. [Epub ahead of print].The molecular mechanisms underlying esophageal adenocarcinoma (EAC) are poorly understood. Blum and colleagues isolated pretreatment EAC patient samples, premalignant Barrett's esophagus, and a subset of EAC cell lines, and performed RNA-sequencing. They identified 21 novel fusion genes, validated in 3-12% of samples. They focused on a fusion between ribosomal S6 kinase (RPS6KB1) and the autophagy regulator, VMP1. RPS6KB1–VMP1 fusions occurred in 10% of their EAC samples, but not in Barrett's or normal esophageal tissues. EAC patients expressing the RPS6KB1–VMP1 fusion also exhibited poorer survival compared with fusion-negative patients. Further, overexpression of RPS6KB1–VMP1 in a Barrett's esophagus cell line increased cell growth. This was especially obvious at higher cell densities, known to induce autophagy. Consistent with this gene fusion expressing a truncated autophagy regulator that drives tumorigenesis, cells expressing RPS6KB1–VMP1 exhibited impaired autophagy.Blum AE, Venkitachalam S, Guo Y, Kieber-Emmons AM, Ravi L, Chandar AK, et al. RNA sequencing identifies transcriptionally viable gene fusions in esophageal adenocarcinomas. Cancer Res 2016;76:5628–33.Using a 3D coculture model, Marusyk and colleagues showed that breast cancer cells in contact with cancer-associated fibroblasts (CAF) displayed subtype-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles. This gene expression signature correlated with clinical outcome in patients and with immune-related differences in the microenvironment. Moreover, the presence of fibroblasts reduced lapatinib accumulation in carcinoma cells and elevated their apoptotic threshold, contributing to therapy resistance. Interestingly, normal breast tissue fibroblasts as well as stromal cultures of brain metastases of breast cancer showed effects similar to CAFs. The authors performed in vitro and in vivo studies, identifying JAK2/STAT3 and hyaluronic acid molecular pathways whose inhibition sensitized HER2+ breast cancer cells to lapatinib. This study identified physiological and clinical relevance of CAF-induced changes in cancer cells, and provides approaches for overcoming microenvironment-mediated therapeutic resistance.Marusyk A, Tabassum D, Janiszewska M, Place A, Trinh A, Rozhok AI, et al. Spatial proximity to fibroblasts impacts molecular features and therapeutic sensitivity of breast cancer cells influencing clinical outcomes. Cancer Res 2016;76:6495–506.Cyclin-dependent kinases 4 and 6, along with their allosteric regulator cyclin D1, are often overexpressed in hormone-receptor positive breast cancers and are key mediators of endocrine resistance. Hortobagyi and colleagues report the prospectively planned interim analysis of a randomized, double-blind, placebo-controlled phase 3 trial conducted in 29 countries where post-menopausal women with hormone receptor-positive, HER2-negative treatment-naïve recurrent or metastatic breast cancer (n = 668) were randomized to receive either the oral CDK4/6 inhibitor ribociclib plus the aromatase inhibitor letrozole or placebo plus letrozole. A progression-free survival benefit was observed across all subgroups of ribociclib-treated patients. Overall responses were impressive, 40.7% in the ribociclib group and 27.5% in the placebo group. Neutropenia, leukopenia, elevated levels of liver function enzymes, and prolonged QTc interval occurred in some patients treated with ribociclib.Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, et al. Ribociclib as first-line iherapy for HR-positive, advanced breast cancer. N Engl J Med 2016 Oct 7. [Epub ahead of print].Metastatic colorectal cancer (mCRC) is treated with bevacizumab, an antibody to VEGF. Examining bevacizumab-treated colorectal liver metastasis from patients and mice, Rahbari and colleagues found increased deposition of extracellular matrix (ECM) components, hyaluronan and sulfated glycosaminoglycans. Therapy-induced ECM deposition significantly increased tumor desmoplasia and stiffness. Mechanistically, bevacizumab-induced hypoxia associated with increased hyaluronic acid deposition, indicating hypoxia as the main driver of the desmoplastic response. Importantly, targeting hyaluronan with hyaluronidase in mice increased perfusion and improved efficacy of chemotherapy in liver metastases after anti-VEGF therapy. This study suggests that increased deposition of noncollagenous ECM in liver metastasis of colorectal cancer limits perfusion and responsiveness to systemic chemotherapy. Thus, enzymatic targeting of hyaluronan represents a potential strategy to enhance the efficacy of systemic treatments for mCRC patients.Rahbari NN, Kedrin D, Incio J, Liu H, Ho WW, Nia HT, et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci Transl Med 2016;8:360ra135.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.